Benzocycloalkylenylamine derivatives as muscarinic receptor antagonists

ABSTRACT

This invention relates to compounds which are generally muscarinic M2/M3 receptor antagonists and which are represented by Formula I:  
                 
 
     wherein X, Y, and Z are O, S, or NR 4 , and the other substituents are as defined in the specification; and prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use as therapeutic agents.

CROSS-REFERENCE TO RELATED INVENTIONS

[0001] This application claims benefit under Title 35 U.S.C. 119(e) ofU.S. Provisional Applications No. 60/207,483 filed May 25, 2000; and No.60/267,617 filed Feb. 9, 2001, all applications are hereby incorporatedby reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to benzocycloalkylenylamine derivatives,associated pharmaceutically acceptable salts, or hydrates thereof, andassociated pharmaceutical compositions and methods for use as M2/M3selective muscarinic receptor antagonists.

BACKGROUND OF THE INVENTION

[0003] Acetylcholine (Ach) is the principal transmitter of theparasympathetic nervous system. The physiological actions of Ach aremediated by activation of either nicotinic or muscarinic receptors. Bothof these receptor classes are heterogeneous: e.g., the muscarinicreceptor family comprises five subtypes (M₁, M₂, M₃, M₄, and M₅) eachencoded by distinct genes and possessing unique pharmacology anddistribution.

[0004] Almost all smooth muscle tissues express both muscarinic M2 andM3 receptors, both of which have a functional role. M2 receptorsoutnumber M3 receptors by a proportion of approximately 4 to 1.Generally, M3 receptors mediate the direct contractile effects ofacetylcholine in the vast majority of smooth muscle tissues. M2receptors, on the other hand, cause smooth muscle contraction indirectlyby inhibiting sympathetically (β-adrenoreceptor)-mediated relaxation.

[0005] Compounds that act as antagonists of muscarinic receptors havebeen used to treat several disease states associated with impropersmooth muscle function. Until recently, most of these compounds havebeen non-selective for the various muscarinic receptor subtypes, leadingto unpleasant anti-cholinergic side-effects such as dry mouth,constipation, blurred vision, or tachycardia. The most common of theseside-effects is dry-mouth resulting from muscarinic receptor blockade inthe salivary gland. Recently developed M2 or M3 specific antagonistshave been shown to have reduced side effects. Evidence suggests thatconcurrent blockade of M2 and M3 receptors could be therapeuticallyeffective in the treatment of disease states associated with smoothmuscle disorders.

[0006] Few M2/M3 selective antagonists have been developed. The presentinvention fills this need by providing these types of antagonists usefulin the treatment of disease states associated with improper smoothmuscle function.

SUMMARY OF THE INVENTION

[0007] This invention relates to compounds comprising Formula I:

[0008] wherein:

[0009] R¹, and R² are independently in each occurrence hydrogen,halogen, (C₁₋₆)-alkyl, —OR′, —SR′, —NR′R″, —SOR′, —SO₂R′, —COOR′,—OCOR′, —OCONR′R″, —OCONR′R″, —OSO₂R′, —OSO₂NR′R″; —NR′SO₂R″, —NR′COR″,—SO₂NR′R″, —SO₂(CH₂)₁₋₃CONR′R″, —CONR′R″, —NR′CONR′R″, cyano, haloalkyl,or nitro;

[0010] R′ and R″ are independently in each occurrence hydrogen,(C₁₋₆)-alkyl, haloalkyl, aryl, heterocyclyl, heteroaryl,aryl-(C₁₋₃)-alkyl, heteroaryl-(C₁₋₃)-alkyl, heterocyclyl-(C₁₋₃)-alkyl,cycloalkylalkyl, cycloalkyl, or R′ and R″ together with the nitrogenthey are attached may also form a 5- to 7-membered ring, optionallyincorporating one additional ring heteroatom chosen from N, O orS(O)₀₋₂;

[0011] R³ is independently in each occurrence (C₁₋₆) alkyl, (C1-6)alkenyl, (C₁₋₆) alkynyl, or cycloalkyl;

[0012] one of X, Y or Z is independently S, O, or N—R⁴, the others areCH₂;

[0013] R⁴ is hydrogen, (C₁₋₆)-alkyl, haloalkyl, aryl(C₁₋₆)alkyl,heteroaryl(C₁₋₆)alkyl, —(C₁₋₆)—CR′R′R′, —COOR′, —SO₂R′, —C(O)R′,—SO₂(CH₂)₀₋₃NR′R″, —CONR′R″, or —PO(OR′)₂, where R′ and R″ are asdefined above;

[0014] m is an integer from 0 to 3 inclusive;

[0015] n is an integer from 1 to 6 inclusive;

[0016] p is an integer from 1 to 3 inclusive; and prodrugs, individualisomers, racemic or non-racemic mixtures of isomers, andpharmaceutically acceptable salts or solvates thereof.

[0017] In a preferred embodiment p is 2.

[0018] In another preferred embodiment p is 2, and one of X, Y or Z isNR⁴ and the others are CH₂; in another embodiment p is 2, and one of X,Y or Z is NR⁴ and the others are CH₂, wherein R⁴ is hydrogen.

[0019] In another preferred embodiment, p is 2 and m is 1; in anotherpreferred embodiment p is 2, m is 1 and Y is NR⁴ and the others are CH₂and in another preferred embodiment p is 2, m is 1 and one of X is NHand the others are CH₂; In another preferred embodiment, p is 2, m is 2;in another preferred embodiment, p is 2, m is 2, and one of X, Y or Z isNR⁴ and the others are CH₂, and in another preferred embodiment p is 2,m is 2, and one of X is NH and the others are CH₂.

[0020] In another embodiment n is 3 and p is 2, in another embodiment nis 3, and one of X, Y or Z is NR⁴ and the others are CH₂; in anotherembodiment n is 3, p is 2 and one of X, Y, or Z is NR⁴ and the othersare CH₂ in another embodiment n is 3, p is 2 and one of X, Y, or Z is NHand the others are CH₂. In another preferred embodiment n is 3, p is 2,m is 2 and one of X, Y, or Z is NR⁴ and the others are CH₂; and inanother preferred embodiment n is 3, p is 2, m is 2, X is NH, and Y andZ are CH₂. In another preferred embodiment n is 3, p is 2, m is 2, Y isNH and X and Z are CH₂. In another preferred embodiment n is 3, p is 2,m is 2, Z is NH and X and Y are CH₂.

[0021] In another embodiment n is 3 and one of X, Y, or Z is NR⁴ and theothers are CH₂.

[0022] In another preferred embodiment p is 2, m is 2, n is 3, one of X,Y or Z is 0 and the others are CH₂. In a preferred embodiment, theinvention further relates to pharmaceutical compositions containing atherapeutically effective amount of at least one compound of Formula I,or prodrugs, individual isomers, racemic or non-racemic mixtures ofisomers, or pharmaceutically acceptable salts or solvates thereof, inadmixture with at least one suitable carrier. In a more preferredembodiment, the pharmaceutical compositions are suitable foradministration to a subject having a disease state which is alleviatedby treatment with a muscarinic M2/M3 receptor antagonist.

[0023] In another aspect, the invention relates to methods for treatinga subject having a disease state that is alleviated by treatment with amuscarinic M2/M3 receptor antagonist, which comprises administering tosuch a subject a therapeutically effective amount of at least a compoundof Formula I. In a preferred embodiment, the subject has a disease statecomprising smooth muscle disorders; preferably genitourinary tractdisorders, respiratory tract disorders, gastrointestinal tractdisorders; more preferably genitourinary tract disorders such asoveractive bladder or detrusor hyperactivity and its symptoms, such asthe changes symptomatically manifested as urgency, frequency, reducedbladder capacity, incontinence episodes, and the like; the changesurodynamically manifested as changes in bladder capacity, micturitionthreshold, unstable bladder contractions, sphincteric spasticity, andthe like; and the symptoms usually manifested in detrusor hyperreflexia(neurogenic bladder), in conditions such as outlet obstruction, outletinsufficency, pelvic hypersensitivity, or in idiopathic conditions suchas detrusor instability, and the like. In another preferred embodiment,the disease comprises respiratory tract disorders such as allergies andasthma. In another preferred embodiment, the disease state comprisesgastrointestinal disorders.

[0024] In another aspect, the invention relates to a process forpreparing a compound of Formula I, which process comprises reacting acompound having a general formula

[0025] with a compound of general formula

[0026] to provide a compound of Formula I:

DETAILED DESCRIPTION OF THE INVENTION

[0027] Definitions

[0028] Unless otherwise stated, the following terms used in thisApplication, including the specification and claims, have thedefinitions given below. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an”, and“the” include plural referents unless the context clearly dictatesotherwise.

[0029] “Lower alkyl” means the monovalent linear or branched saturatedhydrocarbon radical, having from one to six carbon atoms inclusive,unless otherwise indicated. Examples of lower alkyl radicals include,but are not limited to, methyl, ethyl, propyl, isopropyl, 1-ethylpropyl,sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.

[0030] “Substituted lower alkyl” means the lower alkyl as definedherein, including one to three substituents, preferably one substituentsuch as hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano,nitro, thiol. These groups may be attached to any carbon atom of thelower alkyl moiety. Examples of substituted lower alkyl radicalsinclude, but are not limited to, 2-methoxyethyl, 2-hydroxy-ethyl,dimethyl-aminocarbonylmethyl, 4-hydroxy-2,2-dimethyl-butyl,trifluoromethyl, trifluorobutyl and the like.

[0031] “Alkylene” means the divalent linear or branched saturatedhydrocarbon radical, having from one to six carbons inclusive, unlessotherwise indicated. Examples of alkylene radicals include, but are notlimited to, methylene, ethylene, propylene, 2-methyl-propylene,butylene, 2-ethylbutylene, and the like.

[0032] “Alkenyl” means the monovalent linear or branched unsaturatedhydrocarbon radical, containing a double bond and having from two to sixcarbon atoms inclusive, unless otherwise indicated. Examples of alkenylradicals include, but are not limited to, ethenyl, allyl, 1-propenyl,2-butenyl, and the like.

[0033] “Alkynyl” means the monovalent linear or branched unsaturatedhydrocarbon radical, containing a triple bond and having from two to sixcarbon atoms inclusive, unless otherwise indicated. Examples of alkynylradicals include, but are not limited to, ethynyl, 1-propynyl,2-butynyl, propargyl, and the like.

[0034] “Alkoxy” means the radical —O—R, wherein R is a lower alkylradical as defined herein. Examples of alkoxy radicals include, but arenot limited to, methoxy, ethoxy, isopropoxy, and the like.

[0035] “Aryl” means the monovalent aromatic carbocyclic radicalconsisting of one individual ring, or one or more fused rings in whichat least one ring is aromatic in nature, which can optionally besubstituted with one or more, preferably one or two, substituentsselected from hydroxy, cyano, lower alkyl, lower alkoxy, lowerhaloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro,alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl,alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated.Alternatively two adjacent atoms of the aryl ring may be substitutedwith a methylenedioxy or ethylenedioxy group. Examples of aryl radicalsinclude, but are not limited to, phenyl, naphthyl, biphenyl, indanyl,anthraquinolyl, tert-butyl-phenyl, 1,3-benzodioxolyl, and the like.

[0036] “Arylalkyl” means the radical R′R″-, wherein R′ is an arylradical as defined herein, and R″ is an alkyl radical as defined herein.Examples of arylalkyl radicals include, but are not limited to, benzyl,phenylethyl, 3-phenylpropyl, and the like.

[0037] “Cycloalkyl” means the monovalent saturated carbocyclic radicalconsisting of one or more rings, preferably one or two rings, of threeto eight carbons per ring, which can optionally be substituted with oneor more, preferably one or two substitutents, selected from hydroxy,cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo,haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unlessotherwise indicated. Examples of cycloalkyl radicals include, but arenot limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl,cycloheptyl, and the like.

[0038] “Cycloalkylalkyl” means the radical R′R″-, wherein R′ is acycloalkyl radical as defined herein, and R″ is an alkyl radical asdefined herein. Examples of cycloalkylalkyl radicals include, but arenot limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl,and the like.

[0039] “Heteroaryl” means the monovalent aromatic cyclic radical havingone or more rings, preferably one to three rings, of four to eight atomsper ring, incorporating one or more heteroatoms, preferably one or two,within the ring (chosen from nitrogen, oxygen, or sulfur), which canoptionally be substituted with one or more, preferably one or twosubstituents selected from hydroxy, cyano, lower alkyl, lower alkoxy,lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro,alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl,alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated.Examples of heteroaryl radicals include, but are not limited to,imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thienyl, furanyl, pyridinyl,quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl,benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,benzopyranyl, indazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl,naphthyridinyl, benezenesulfonyl-thiophenyl, and the like.

[0040] “Heteroarylalkyl” (or “heteroaralkyl”) means the radical of theformula R′R″, wherein R′ is a heteroaryl radical as defined herein, andR″ is an alkylene radical as defined herein. Examples of heteroarylalkyradicals include, but are not limited to, 2-imidazolylmethyl,3-pyrrolylethyl, and the like.

[0041] “Heterocyclyl” means the monovalent saturated cyclic radical,consisting of one or more rings, preferably one to two rings, of threeto eight atoms per ring, incorporating one or more ring heteroatoms(chosen from N, O or S(O)₀₋₂), and which can optionally be substitutedwith one or more, preferably one or two substituents selected fromhydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy,alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino,alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl,arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino,alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino,arylcarbonylamino, unless otherwise indicated. Examples of heterocyclicradicals include, but are not limited to, morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholinyl,quinuclidinyl, and the like.

[0042] “Heterocycloalkyl” (or “heterocyclylalkyl”) means the radical ofthe formula R′R″, wherein R′ is a heterocyclic radical as definedherein, and R″ is an alkylene radical as defined herein. Examples ofheterocycloalkyl radicals include, but are not limited to,1-piperazinylmethyl, 2-morpholinomethyl, and the like.

[0043] “Halogen” means the radical fluoro, bromo, chloro, and/or iodo.

[0044] “Haloalkyl” means the lower alkyl radical as defined hereinsubstituted in any position with one or more halogen atoms as definedherein. Examples of haloalkyl radicals include, but are not limited to,1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0045] “Hydroxyalkyl” means the lower alkyl radical as defined herein,substituted with one or more hydroxy groups. Examples of hydroxyalkylradicals include, but are not limited to, hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and2-(hydroxymethyl)-3-hydroxypropyl, and the like.

[0046] “Acyloxy” means the radical —OC(O)R, wherein R is a lower alkylradical as defined herein. Examples of acyloxy radicals include, but arenot limited to, acetoxy, propionyloxy, and the like.

[0047] “Alkoxycarbonyl” or “alkyl ester” means the radical —C(O)—O—R,wherein R is a lower alkyl radical as defined herein. Examples ofalkoxycarbonyl radicals include, but are not limited to,methoxycarbonyl, ethoxycarbonyl, sec-butoxycarbonyl,isopropyloxycarbonyl, and the like.

[0048] “Aryloxycarbonyl” or “aryl ester” means the radical —C(O)—O—R,wherein R is an aryl radical as defined herein. Examples ofaryloxycarbonyl radicals include, but are not limited to phenyl ester,naphthyl ester, and the like.

[0049] “Arylalkoxycarbonyl” or “arylalkyl ester” means the radical—C(O)—O—RR′, wherein R is a lower alkyl radical and R′ is an arylradical as defined herein. Examples of aryloxycarbonyl radicals include,but are not limited to benzyl ester, phenyl ethyl ester, and the like.

[0050] “Alkylcarbonyl” (or “acyl”) means the radical R—C(O)—, wherein Ris a lower alkyl radical as defined herein. Examples of alkylcarbonylradicals include, but are not limited to, acetyl, propionyl, n-butyryl,sec-butyryl, t-butyryl, iso-propionyl and the like.

[0051] “Arylcarbonyl” means the radical R—C(O)—, wherein R is an arylradical as defined herein. Examples of arylcarbonyl radicals include,but are not limited to, benzoyl, naphthoyl, and the like.

[0052] “Arylalkylcarbonyl” (or “aralkylcarbonyl”) means the radicalR—C(O)—, wherein R is an arylalkyl radical as defined herein. Examplesof arylalkylcarbonyl radicals include, but are not limited to,phenylacetyl, and the like.

[0053] “Heteroarylcarbonyl” means the radical R—C(O)—, wherein R is anheteroaryl radical as defined herein. Examples of heteroarylcarbonylradicals include, but are not limited to, pyridinoyl,3-methylisoxazoloyl, isoxazoloyl, thienoyl, furoyl, and the like.

[0054] “Heterocyclylcarbonyl” (or “heterocyclocarbonyl”) means theradical R—C(O)—, wherein R is an heterocyclyl radical as defined herein.Examples of heterocyclylcarbonyl radicals include, but are not limitedto, piperazinoyl, morpholinoyl, pyrrolindinoyl, and the like.

[0055] “Cycloalkylcarbonyl” means the radical R—C(O)—, wherein R is acycloalkyl radical as defined herein. Examples of cycloalkylcarbonylradicals include, but are not limited to, cyclobutanoyl, cyclopentanoyl,cyclohexanoyl, and the like.

[0056] “Alkylaminocarbonyl” means the radical —C(O)NR′R″, wherein R′ islower alkyl as defined herein, and R″ is hydrogen or lower alkyl asdefined herein. Examples of alkylaminocarbonyl include, but are notlimited to methylaminocarbonyl, dimethylaminocarbonyl,t-butylaminocarbonyl, n-butylaminocarbonyl, iso-propylaminocarbonyl andthe like.

[0057] “Arylaminocarbonyl” means the radical —C(O)NR′R″, wherein R′ isaryl as defined herein, and R″ is hydrogen or aryl as defined herein.Examples of arylaminocarbonyl include, but are not limited tophenylaminocarbonyl, methoxyphenylaminocarbonyl, diphenylaminocarbonyl,dimethoxyphenylaminocarbonyl, and the like.

[0058] “Hieteroarylaminocarbonyl” means the radical —C(O)NR′R″, whereinR′ is heteroaryl as defined herein, and R″ is hydrogen or heteroaryl asdefined herein. Examples of heteroarylaminocarbonyl include, but are notlimited to pyridinylaminocarbonyl, thienylaminocarbonyl,furanylaminocarbonyl, and the like.

[0059] “Alkylcarbonylamino” means the radical —NC(O)R′, wherein R′ islower alkyl as defined herein. Examples of alkylcarbonylamino include,but are not limited to methylcarbonylamino, iso-propylcarbonylamino,t-butylcarbonylamino, and the like.

[0060] “Arylcarbonylamino” means the radical —NC(O)R′, wherein R′ isaryl as defined herein. Examples of arylcarbonylamino include, but arenot limited to phenylcarbonylamino, tosylcarbonylamino, and the like.

[0061] “Alkylcarbamoyl” means the radical —OC(O)NR′R″, wherein R′ islower alkyl as defined herein, and R″ is hydrogen or lower alkyl asdefined herein. Examples of alkylcarbamoyl include, but are not limitedto methylcarbamoyl, ethylcarbamoyl, and the like.

[0062] “Arylcarbamoyl” means the radical —OC(O)NR′R″, wherein R′ islower aryl as defined herein, and R″ is hydrogen or aryl as definedherein. Examples of arylcarbamoyl include, but are not limited tophenylcarbamoyl, naphthylcarbamoyl, and the like.

[0063] “Arylalkylcarbamoyl” means the radical —OC(O)NHR′R″, wherein R′is lower alkyl as defined herein, and R″ is aryl as defined herein.Examples of arylalkylcarbamoyl include, but are not limited tobenzylcarbamoyl, phenylethylcarbamoyl, and the like.

[0064] “Alkylaminosulfonyl” means the radical —S(O)₂NR′R″, wherein R′ islower alkyl as defined herein, and R″ is hydrogen or lower alkyl asdefined herein. Examples of alkylaminosulfonyl include, but are notlimited to methylaminosulfonyl, dimethylaminosulfonyl, and the like.

[0065] “Arylaminosulfonyl” means the radical —S(O)₂NR′R″, wherein R′ isaryl as defined herein, and R″ is hydrogen or aryl as defined herein.Examples of arylaminosulfonyl include, but are not limited tophenylaminosulfonyl, methoxyphenylaminosulfonyl, and the like.

[0066] “Heteroarylaminosulfonyl” means the radical —S(O)₂NR′R″, whereinR′ is heteroaryl as defined herein, and R″ is hydrogen or heteroaryl asdefined herein. Examples of heteroarylaminosulfonyl include, but are notlimited to thienylaminosulfonyl, piperidinylaminosulfonyl,furanylaminosulfonyl, imidazolylaminosulfonyl and the like.

[0067] “Alkylsulfonylamino” means the radical —NS(O)₂R′, wherein R′ islower alkyl as defined herein. Examples of alkylsulfonylamino include,but are not limited to methylsulfonylamino, propylsulfonylamino, and thelike.

[0068] “Arylsulfonylamino” means the radical —NS(O)₂R′, wherein R′ isaryl as defined herein. Examples of arylsulfonylamino include, but arenot limited to phenylsulfonylamino, naphthylsulfonylamino, and the like.

[0069] “Alkylsulfonyl” means the radical —S(O)₂R, wherein R is loweralkyl or a substituted lower alkyl as defined herein. Examples ofalkylsulfonyl include, but are not limited to methylsulfonyl,trifluoromethylsulfonyl, propylsulfonyl, and the like.

[0070] “Arylsulfonyl” means the radical —S(O)₂R, wherein R is aryl asdefined herein. Examples of arylsulfonyl include, but are not limited tophenylsulfonyl, nitrophenylsulfonyl, methoxyphenylsulfonyl,3,4,5-trimethoxyphenylsulfonyl, and the like.

[0071] “Heteroarylsulfonyl” means the radical —S(O)₂R, wherein R isheteroaryl as defined herein. Examples of heteroarylsulfonyl include,but are not limited to thienylsulfonyl, furanylsulfonyl,imidazolylsulfonyl, N-methylimidazolylsulfonyl and the like.

[0072] “Heterocyclylsulfonyl” means the radical —S(O)₂R, wherein R isheterocyclyl as defined herein. Examples of heterocyclylsulfonylinclude, but are not limited to piperidinylsulfonyl,piperazinylsulfonyl, and the like.

[0073] “Alkylsulfonyloxy” means the radical —O S(O)₂R, wherein R islower alkyl or substituted lower alkyl as defined herein. Examples ofalkylsulfonyloxy include, but are not limited to methylsulfonyloxy,trifluoromethylsulfonyloxy, propylsulfonyloxy, and the like.

[0074] “Arylsulfonyloxy” means the radical —O S(O)₂R, wherein R is arylas defined herein. Examples of arylsulfonyloxy include, but are notlimited to benzenesulfonyloxy., 4-chloro-benzenesullfonyloxy, and thelike

[0075] “Heteroarylsulfonyloxy” means the radical —O S(O)₂R, wherein R ishetroaryl as defined herein. Examples of hetroarylsulfonyloxy include,but are not limited to thienylsulfonyloxy, and the like.

[0076] “Heterocyclylsulfonyloxy” means the radical —O S(O)₂R, wherein Ris heterocycyl as defined herein. Examples of heterocyclylsulfohyloxyinclude, but are not limited to 3,5, dimethyl-isoxazolesulfonyloxy,pyrrolidinylsulfonyloxy, and the like

[0077] “Optional” or “optionally” means that the subsequently describedevent or circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optional bond” means that the bondmay or may not be present, and that the description includes single,double, or triple bonds.

[0078] “Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under alkylating conditions. Examples of leavinggroups include, but are not limited to, halogen, alkyl- orarylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

[0079] “Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive oxygen atoms present in thereactants. Acceptable protective groups for alcoholic or phenolichydroxyl groups, which may be removed successively and selectivelyincludes groups protected as acetates, haloalkyl carbonates, benzylethers, alkylsilyl ethers, heterocyclyl ethers, and methyl or alkylethers, and the like. Protective or blocking groups for carboxyl groupsare similar to those described for hydroxyl groups, preferablytert-butyl, benzyl or methyl esters. Examples of protecting groups canbe found in T. W. Greene et al., Protective Groups in Organic Chemistry,(J. Wiley, 2^(nd) ed. 1991) and Harrison et al., Compendium of SyntheticOrganic Methods, Vols. 1-8 (J. Wiley and Sons 1971-1996).

[0080] “Amino-protecting group” means the protecting group that refersto those organic groups intended to protect the nitrogen atom againstundesirable reactions during synthetic procedures and includes, but isnot limited to, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ),p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. It ispreferred to use either BOC or CBZ as the amino-protecting group becauseof the relative ease of removal, for example by mild acids in the caseof BOC, e.g., trifluoroacetic acid or hydrochloric acid in ethylacetate; or by catalytic hydrogenation in the case of CBZ.

[0081] “Deprotection” or “deprotecting” means the process by which aprotective group is removed after the selective reaction is completed.Certain protective groups may be preferred over others due to theirconvenience or relative ease of removal. Deprotecting reagents forprotected hydroxyl or carboxyl groups include potassium or sodiumcarbonates, lithium hydroxide in alcoholic solutions, zinc in methanol,acetic acid, trifluoroacetic acid, palladium catalysts, or borontribromide, and the like.

[0082] “Isomerism” means compounds that have identical molecularformulae but that differ in the nature or the sequence of bonding oftheir atoms or in the arrangement of their atoms in space. Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers”. Stereoisomers that are not mirror images of one anotherare termed “diastereoisomers”, and stereoisomers that arenon-superimposable mirror images are termed “enantiomers”, or sometimesoptical isomers. A carbon atom bonded to four nonidentical substituentsis termed a “chiral center”.

[0083] “Chiral isomer” means a compound with one chiral center. It hastwo enantiomeric forms of opposite chirality and may exist either as anindividual enantiomer or as a mixture of enantiomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”. A compound that has more thanone chiral center has 2^(n-1) enantiomeric pairs, where n is the numberof chiral centers. Compounds with more than one chiral center may existas either an individual diastereomer or as a mixture of diastereomers,termed a “diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al.(1966) Angew. Chem. Inter. Edit., 5, 385; errata 511; Cahnet al. (1966) Angew. Chem., 78, 413; Cahn and Ingold (1951) J. Chem.Soc. (London), 612; Cahn et al. (1956) Experientia, 12, 81; Cahn, J.(1964) Chem. Educ., 41, 116).

[0084] “Geometric Isomers” means the diastereomers that owe theirexistence to hindered rotation about double bonds. These configurationsare differentiated in their names by the prefixes cis and trans, or Zand E, which indicate that the groups are on the same or opposite sideof the double bond in the molecule according to the Cahn-Ingold-Prelogrules.

[0085] “Atropic isomers” means the isomers owing their existence torestricted rotation caused by hindrance of rotation of large groupsabout a central bond.

[0086] “Substantially pure” means at least about 80 mole percent, morepreferably at least about 90 mole percent, and most preferably at leastabout 95 mole percent of the desired enantiomer or stereoisomer ispresent.

[0087] “Pharmaceutically acceptable” means that which is useful inpreparing a pharmaceutical composition that is generally safe,non-toxic, and neither biologically nor otherwise undesirable andincludes that which is acceptable for veterinary as well as humanpharmaceutical use.

[0088] “Pharmaceutically acceptable salts” of a compound means saltsthat are pharmaceutically acceptable, as defined herein, and thatpossess the desired pharmacological activity of the parent compound.Such salts include:

[0089] (1) acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citricacid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconicacid, glutamic acid, glycolic acid, hydroxynaphthoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonicacid, propionic acid, salicylic acid, succinic acid,dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid,trimethylacetic acid, trifluoroacetic acid, and the like; or

[0090] (2) salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic or inorganic base. Acceptable organic bases includediethanolamine, ethanolamine, N-methylglucamine, triethanolamine,tromethamine, and the like. Acceptable inorganic bases include aluminumhydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate andsodium hydroxide.

[0091] The preferred pharmaceutically acceptable salts are the saltsformed from hydrochloric acid, trifluoroacetic acid,dibenzoyl-L-tartaric acid, and phosphoric acid.

[0092] It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

[0093] “Crystal forms” (or polymorphs) means crystal structures in whicha compound can crystallize in different crystal packing arrangements,all of which have the same elemental composition. Different crystalforms usually have different X-ray diffraction patterns, infraredspectra, melting points, density hardness, crystal shape, optical andelectrical properties, stability and solubility. Recrystallizationsolvent, rate of crystallization, storage temperature, and other factorsmay cause one crystal form to dominate.

[0094] “Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate. “Prodrug” means a pharmacologicallyinactive form of a compound which must be metabolized in vivo, e.g., bybiological fluids or enzymes, by a subject after administration into apharmacologically active form of the compound in order to produce thedesired pharmacological effect. The prodrug can be metabolized beforeabsorption, during absorption, after absorption, or at a specific site.Although metabolism occurs for many compounds primarily in the liver,almost all other tissues and organs, especially the lung, are able tocarry out varying degrees of metabolism. Prodrug forms of compounds maybe utilized, for example, to improve bioavailability, improve subjectacceptability such as by masking or reducing unpleasant characteristicssuch as bitter taste or gastrointestinal irritability, alter solubilitysuch as for intravenous use, provide for prolonged or sustained releaseor delivery, improve ease of formulation, or provide site-specificdelivery of the compound. Prodrugs are described in The OrganicChemistry of Drug Design and Drug Action, by Richard B. Silverman,Academic Press, San Diego, 1992. Chapter 8: “Prodrugs and Drug deliverySystems” pp.352-401; Design of Prodrugs, edited by H. Bundgaard,Elsevier Science, Amsterdam, 1985; Design of BiopharmaceuticalProperties through Prodrugs and Analogs, Ed. by E. B. Roche, AmericanPharmaceutical Association, Washington, 1977; and Drug Delivery Systems,ed. by R. L. Juliano, Oxford Univ. Press, Oxford, 1980.

[0095] “Subject” means mammals and non-mammals. Mammals means any memberof the Mammalia class including, but not limited to, humans, non-humanprimates such as chimpanzees and other apes and monkey species; farmanimals such as cattle, horses, sheep, goats, and swine; domesticanimals such as rabbits, dogs, and cats; laboratory animals includingrodents, such as rats, mice, and guinea pigs; and the like. Examples ofnon-mammals include, but are not limited to, birds, and the like.

[0096] “Therapeutically effective amount” means an amount of a compoundthat, when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,and disease state being treated, the severity or the disease treated,the age and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

[0097] “Pharmacological effect” as used herein encompasses effectsproduced in the subject that achieve the intended purpose of a therapy.In one preferred embodiment, a pharmacological effect means that primaryindications of the subject being treated are prevented, alleviated, orreduced. For example, a pharmacological effect would be one that resultsin the prevention, alleviation or reduction of primary indications in atreated subject. In another preferred embodiment, a pharmacologicaleffect means that disorders or symptoms of the primary indications ofthe subject being treated are prevented, alleviated, or reduced. Forexample, a pharmacological effect would be one that results in theprevention or reduction of primary indications in a treated subject.

[0098] “Disease state” means any disease, condition, symptom, orindication.

[0099] “Treating” or “treatment” of a disease state includes:

[0100] (1) preventing the disease state, i.e. causing the clinicalsymptoms of the disease state not to develop in a subject that may beexposed to or predisposed to the disease state, but does not yetexperience or display symptoms of the disease state;

[0101] (2) inhibiting the disease state, i.e., arresting the developmentof the disease state or its clinical symptoms; or

[0102] (3) relieving the disease state, Le., causing temporary orpermanent regression of the disease state or its clinical symptoms.

[0103] “Antagonist” means a molecule such as a compound, a drug, anenzyme inhibitor, or a hormone, that diminishes or prevents the actionof another molecule or receptor site.

[0104] “Disorders of the urinary tract” or “uropathy” usedinterchangeably with “symptoms of the urinary tract” means thepathologic changes in the urinary tract. Symptoms of the urinary tractinclude overactive bladder (also known as detrusor hyperactivity),outlet obstruction, outlet insufficiency, and pelvic hypersensitivity.

[0105] “Overactive bladder” or “Detrusor hyperactivity” includes, but isnot limited to, the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity, and the like; and the symptoms usuallymanifested in detrusor hyperreflexia (neurogenic bladder), in conditionssuch as outlet obstruction, outlet insufficency, pelvichypersensitivity, or in idiopathic conditions such as detrusorinstability, and the like.

[0106] “Outlet obstruction” includes, but is not limited to, benignprostatic hypertrophy (BPH), urethral stricture disease, tumors and thelike. It is usually symptomatically manifested as obstructive (low flowrates, difficulty in initiating urination, and the like), or irritative(urgency, suprapubic pain, and the like).

[0107] “Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, or mixed incontinence.It is usually symptomatically manifested as stress incontinence.

[0108] “Pelvic Hypersensitivity” includes but is not limited to, pelvicpain, interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia,urethritis, orchidalgia, and the like. It is symptomatically manifestedas pain, inflammation or discomfort referred to the pelvic region, andusually includes symptoms of overactive bladder.

[0109] Nomenclature

[0110] The naming of the compounds of this invention is illustratedbelow:

[0111] In general, the nomenclature used in this Application is based onAUTONOM™, a Beilstein Institute computerized system for the generationof IUPAC systematic nomenclature. A compound of Formula I wherein R¹ andR² are methoxy, R³ is propyl, p is 2, n is 3, m is 2, X and Y are CH₂and Z is NH is named:4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one.

[0112] Preferred Compounds

[0113] Among compounds of the present invention set forth in the Summaryof the Invention, certain compounds of Formula I, or prodrugs,individual isomers, racemic or non-racemic mixtures of isomers, orpharmaceutically acceptable salts or solvates thereof, are preferred:

[0114] R¹, and R2 are independently in each occurrence preferablyhydrogen, halogen, (C₁₋₆)-alkyl, alkoxy, alkylsulfonyl, oralkylsulfonyloxy, and more preferably hydrogen, methoxy, methylsulfonyl,or methylsulfonyloxy.

[0115] R³ is independently in each occurrence preferably lower alkyl,lower alkenyl or lower alkynyl, more preferably ethyl, propyl,iso-propyl, allyl or propargyl, and even more preferably ethyl orpropyl.

[0116] p is preferably 1 to 3, more preferably 1 to 2, and even morepreferably 2.

[0117] m is preferably 0 to 3; more preferably 1 to 2; and even morepreferably 2.

[0118] n is preferably 1 to 6; more preferably 1 to 3; and even morepreferably 3.

[0119] one of X, Y, or Z is independently in each occurrence preferablyS, O, or NR⁴, most preferably NR⁴, and even more preferably NH.

[0120] Other preferred compounds of the present invention include thepharmaceutically acceptable salts of the compounds of the presentinvention wherein the pharmaceutically acceptable salts are formed fromhydrochloric acid, 2,2,2-trifluoroacetic acid, dibenzoyl-L-tartaricacid, sodium, or phosphoric acid, more preferably the salts are formedfrom hydrochloric acid, 2,2,2-trifluoroacetic acid.

[0121] Exemplary particularly preferred compounds, or prodrugs,individual isomers, racemic or non-racemic mixtures of isomers, orpharmaceutically acceptable salts or solvates thereof, include:

[0122] 3,5-dimethyl-isoxazole-4-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester;

[0123]4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;

[0124]4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one;

[0125]4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one;

[0126]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;

[0127]1-{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;or

[0128]3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one.

General Synthetic Reaction Schemes

[0129] Compounds of the present invention may be made by the methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

[0130] The starting materials and reagents used in preparing thesecompounds generally are either available from commercial suppliers, suchas Aldrich Chemical Co., or are prepared by methods known to thoseskilled in the art following procedures set forth in references such asFieser and Fieser (1991) Reagents for Organic Synthesis; Wiley & Sons:N.Y., Volumes 1-15; Rodd (1989) Chemistry of Carbon Compounds, ElsevierScience Publishers, Volumes 1-5 and Supplementals; and (1991) OrganicReactions, Wiley & Sons: N.Y., Volumes 1-40. The following syntheticreaction schemes are merely illustrative of some methods by which thecompounds of the present invention may be synthesized, and variousmodifications to these synthetic reaction schemes may be made and willbe suggested to one skilled in the art having referred to the disclosurecontained in this Application.

[0131] The starting materials and the intermediates of the syntheticreaction schemes may be isolated and purified if desired usingconventional techniques, including but not limited to filtration,distillation, crystallization, chromatography, and the like. Suchmaterials may be characterized using conventional means, includingphysical constants and spectral data.

[0132] Unless specified to the contrary, the reactions described hereinpreferably take place at atmospheric pressure over a temperature rangefrom about −78° C. to about 150° C., more preferably from about 0° C. toabout 125° C., and most preferably and conveniently at about room (orambient) temperature, e.g., about 20° C.

Scheme A

[0133] Scheme A, in general, describes a method of preparing a compoundof Formula I wherein X, Y, Z, R¹, R², R³, p, m, and n are as describedin the Summary of the Invention.

[0134] A compound of Formula I can generally be prepared by coupling acarboxaldehyde 1 with a benzocyclylamine 2 under reductive aminationconditions. Suitable reducing conditions include sodiumtriacetoxyborohydride, sodium cyanoborohydride, titanium isopropoxideand sodium cyanoborohydride, hydrogen and a metal catalyst and hydrogentransfering agents such as cyclohexene, formic acid and its salts, zincand hydrochloric acid, formic acid, or borane dimethylsulfide followedby treatment with formic acid. Suitable inert organic solvents for thereaction include dichloromethane, 1,2-dichloroethane, tetrahydrofuran,alcohols, or ethyl acetate, and the like. Preferably the reaction iscarried out under basic conditions with sodium triacetoxyborohydride in1,2-dichloroethane.

[0135] Reductive amination procedures are described in the chemicalliterature. For example, (1996) J. Org. Chem., 61, 3849 and (1996)Tetrahedron Letters, 37, 3977, describe methods utilizing sodiumtriacetoxyborohydride as a reagent for the reductive amination ofaldehydes with a wide variety of amines. For example, (1971) J. Am.Chem. Soc., 93, 2897 and (1988) Org. Synth. Coll., 6, 499 describemethods utilizing sodium cyanoborohydride as reagent for reductiveamination of carbonyl compounds.

[0136] The conventional starting materials of Scheme A are commerciallyavailable or are known to, or can readily be synthesized by those ofordinary skill in the art. For example, the starting carboxaldehyde 1can readily be synthesized as shown by the following reaction schemes(1), (2), and (3):

[0137] A carboxaldehyde 1 wherein X, Y, Z, m, and n are as described inthe Summary of the Invention can be prepared by reacting the amido groupof compound a with an alkylating agent of the formula L(CH₂)_(n)CH═CH₂wherein L is a leaving group such as halogen or methanesulfonyloxy,preferably chloro, under basic conditions to obtain a compound b. Thealkylation reaction is followed by the oxidation/cleavage of theterminal alkene group of compound b to an aldehyde group to obtain acarboxaldehyde 1. Various oxidizing agents used in theoxidation/cleavage of alkenes to aldehydes are described in the chemicalliterature. For example, (1956) J. Org. Chem., 21, 478 describes methodsutilizing osmium tetroxide and sodium (meta)periodate; (1982) Syn.Comm., 12,1063 describes methods utilizing potassium permanganate andsodium(meta)periodate; (1987) J. Org. Chem., 52, 3698 describes methodsutilizing potassium permanganate and silica gel; (1958) Chem. Rev., 58,925 describes methods utilizing ozone; (1986) J. Org. Chem., 51, 3213describes methods utilizing potassium permanganate alone; (1987) J. Org.Chem., 52, 2875 describes methods utilizing sodium (meta)periodate andcatalytic ruthenium. Preferably the reaction is carried out with osmiumtetroxide and sodium (meta)periodate or ozone.

[0138] Alternatively, a carboxaldehyde 1 wherein X, Y, Z, m, and n areas described in the Summary of the Invention can be prepared by reactingthe free amine group of compound a with an alkylating agent of theformula L(CH₂)_(n)C(OR)₂ wherein R is lower alkyl and L is a leavinggroup such as halogen, preferably bromo, to obtain a compound c. Thealkylation reaction is followed by the hydrolysis of the acetal group ofcompound c under acidic conditions to obtain a carboxaldehyde 1.

[0139] Alternatively, a carboxaldehyde 1 wherein X, Y, Z, m, and n areas described in the Summary of the Invention, can be prepared bytreating an aminoacetal d wherein R is lower alkyl with an appropriateacylating agent such as acylating agents of the formula L(CH₂)_(n)COL′,or L(CH₂)_(n)OCOL′, or L(CH₂)_(n)N═C═O wherein in each instance L′ is aleaving group such as halogen, preferably chloro, to obtain compound e.The acylating reaction is followed by the internal N-alkylation ofcompound e, and the subsequent hydrolysis of the acetal group ofcompound f to obtain a carboxaldehyde 1.

[0140] For example, the starting benzocyclylamine 2 can be synthesizedas shown by the following reaction scheme (4):

[0141] A benzocyclylamine 2 wherein R¹, R², and R³, are as described inthe Summary of the Invention may be prepared by treatment of abenzocyclylone R1, g with a primary amine of the formula R³NH₂ underreductive amination conditions. Various methods for the synthesis of abenzocyclylamine 2 are described in the chemical literature, forexample, (1980) J. Med. Chem., 23, 745-749; (1981) J. Med. Chem.,24,429-434; (1989) J. Med. Chem., 32,2128-2134, (1996) J. Org. chem.,61, 3849-3862. and (1997) Bioorg. Med Chem. Lett., 15,1995-1998.

Scheme B

[0142] Scheme B, in particular, describes a method of preparing acompound of Formula I wherein X is NR⁴, O, or S; Y and Z are each CH₂;and R¹, R², R³, R⁴, p, m, and n are as described in the Summary of theInvention.

[0143] A compound of Formula IB can be prepared by proceeding asdescribed in Scheme A. Preferably, a compound of Formula IB can beprepared by reacting a carboxaldehyde 1b with a benzocyclylamine 2 underreductive amination conditions as described in Scheme A.

[0144] Exemplary preparations of a compound of Formula 1B are given inExample 1.

Scheme C

[0145] Scheme C, in particular, describes a method of preparing acompound of Formula I wherein X and Z are each CH₂, Y is NR⁴, O or S,and R¹, R², R³, R⁴, p, m, and n are as described in the Summary of theInvention.

[0146] A compound of Formula IC can be prepared by proceeding asdescribed in Scheme A.

[0147] Preferably, a compound of Formula I wherein Y is O or S can beprepared by reacting a carboxaldehyde 1c with a benzocyclylamine 2 underreductive amination conditions as described in Scheme A.

[0148] Alternatively, a compound of Formula I wherein Y is NR⁴ can alsobe prepared by coupling a nitrogen-protected carboxaldehyde 1 d whereinP is a suitable nitrogen-protecting group with a benzocylcylamine 2 inconditions as described above. This reaction is followed by removing thenitrogen-protecting group of compound 3 under acidic conditions toobtain a compound of Formula I wherein Y is NH. The compound of FormulaI wherein Y is NH may then be further reacted with an appropriatealkylating agent, acylating agent, or sulfonylating agent by proceduresknown to one skilled in the art to obtain a compound of Formula Iwherein Y is NR⁴ wherein R⁴ is other than H.

[0149] Exemplary preparations of a compound of Formula IC are given inExamples 2, 3, and 4.

Scheme D

[0150] Scheme D, in particular, describes a method of preparing acompound of Formula I wherein X and Y are each CH₂, and Z is NR⁴, O orS, and R¹, R², R³, R⁴, p, m, and n are as described in the Summary ofthe Invention.

[0151] A compound of Formula ID can be prepared by proceeding asdescribed in Scheme A.

[0152] Preferably, a compound of Formula I wherein Z is O or S can beprepared by reacting a carboxaldehyde 1e with a benzocyclylamine 2 underconditions as described in Scheme A.

[0153] Alternatively, a compound of Formula I wherein Z is NR⁴ can beprepared by coupling an amino-protected carboxaldehyde 1 f wherein P isa suitable nitrogen-protecting group with a benzocyclylamine 2 asmentioned above. This reaction is followed by removing thenitrogen-protecting group of compound 4 under acidic conditions toobtain a compound of Formula I wherein Z is NH. Optionally the compoundof Formula I wherein Z is NH may then be further reacted with anappropriate alkylating agent, acylating agent, or sulfonylating agent byprocedures known to one skilled in the art to obtain a compound ofFormula I wherein Z is NR⁴ wherein R⁴ is other than H.

[0154] Exemplary preparations of a compound of Formula ID are given inExamples 5, 6, and 7.

General Utility

[0155] Compounds that act as antagonists of muscarinic receptors havebeen used to treat several disease states associated with impropersmooth muscle function. Until recently, most of these compounds havebeen non-selective for the various muscarinic receptor subtypes, leadingto unpleasant anti-cholinergic side-effects such as dry mouth,constipation, blurred vision or tachycardia, the most common of which isdry-mouth that results from muscarinic receptor blockade in the salivarygland. Recently developed M2 or M3 specific antagonists have been shownto have reduced side effects. Evidence suggests that concurrent blockadeof M2 and M3 receptors could be therapeutically effective in thetreatment of disease states associated with smooth muscle disorders,such as genitourinary tract disorders, respiratory tract disorders,gastrointestinal tract disorders, and smooth muscle disorders.Genitourinary tract disorders treatable with compounds of this inventionspecifically include overactive bladder or detrusor hyperactivity andits symptoms such as the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity, and the like; and the symptoms usuallymanifested in detrusor hyperreflexia (neurogenic bladder), in conditionssuch as outlet obstruction, outlet insufficency, pelvichypersensitivity, or in idiopathic conditions such as detrusorinstability, and the like.

[0156] Gastrointestinal tract disorders treatable with compounds of thisinvention specifically include irritable bowel syndrome, diverticulardisease, achalasia, gastrointestinal hypermotility disorders, anddiarrhea. Respiratory tract disorders treatable with compounds of thisinvention specifically include chronic obstructive pulmonary disease,asthma and pulmonary fibrosis.

[0157] These and other therapeutic uses are described, for example, inGoodman & Gilman, (1996) The Pharmacological Basis of Therapeutics,ninth edition, McGraw-Hill, N.Y., Chapter 26:601-616; and Coleman, R.A., (1994) Pharmacological Reviews, 46:205-229.

Testing

[0158] The compounds of this invention are muscarinic receptorantagonists. The muscarinic receptor affinity of test compounds can bedetermined by an in vitro receptor binding assay which utilizes a cellmembrane preparation from the Chinese hamster ovary cells expressing therecombinant human muscarinic receptors (M₁-M₅), and is described in moredetail in Example 15.

[0159] The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated saliva secretion in anesthetizedrats, and is described in more detail in theOxotremorine/Pilocarpine-induced salivation (OIS/PIS) model inanesthetized rats, Example 16.

[0160] The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated bladder contraction in anesthetizedrats, and is described in more detail in the inhibition ofvolume-induced contractions assay, Example 17.

[0161] The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated bladder contraction and salivasecretion in anesthetized dogs, and is described in more detail inExample 18.

Administration and Pharmaceutical Composition

[0162] The present invention includes pharmaceutical compositionscomprising at least one compound of the present invention, or a prodrug,an individual isomer, a racemic or non-racemic mixture of isomers or apharmaceutically acceptable salt, or solvate thereof together with atleast one pharmaceutically acceptable carrier, and optionally othertherapeutic and/or prophylactic ingredients.

[0163] In general, the compounds of the present invention will beadministered in a therapeutically effective amount by any of theaccepted modes of administration for agents that serve similarutilities. Suitable dosage ranges are typically 1-500 mg daily,preferably 1-100 mg daily, and most preferably 1-30 mg daily, dependingupon numerous factors such as the severity of the disease to be treated,the age and relative health of the subject, the potency of the compoundused, the route and form of administration, the indication towards whichthe administration is directed, and the preferences and experience ofthe medical practitioner involved. One of ordinary skill in the art oftreating such diseases will be able, without undue experimentation andin reliance upon personal knowledge and the disclosure of thisApplication, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease. In general,compounds of the present invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sublingual), rectal, nasal, topical, pulmonary, vaginal, orparenteral (including intramuscular, intraarterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is generally oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.

[0164] A compound or compounds of the present invention, together withone or more conventional adjuvants, carriers, or diluents, may be placedinto the form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

[0165] The compounds of the present invention may be formulated in awide variety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

[0166] Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0167] The compounds of the present invention may be formulated forparenteral administration (e.g., by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, for example solutions in aqueous polyethylene glycol. Examplesof oily or nonaqueous carriers, diluents, solvents or vehicles includepropylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil),and injectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0168] The compounds of the present invention may be formulated fortopical administration to the epidermis as ointments, creams or lotions,or as a transdermal patch. Ointments and creams may, for example, beformulated with an aqueous or oily base with the addition of suitablethickening and/or gelling agents. Lotions may be formulated with anaqueous or oily base and will in general also containing one or moreemulsifying agents, stabilizing agents, dispersing agents, suspendingagents, thickening agents, or coloring agents. Formulations suitable fortopical administration in the mouth include lozenges comprising activeagents in a flavored base, usually sucrose and acacia or tragacanth;pastilles comprising the active ingredient in an inert base such asgelatin and glycerin or sucrose and acacia; and mouthwashes comprisingthe active ingredient in a suitable liquid carrier.

[0169] The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

[0170] The compounds of the present invention may be formulated fornasal administration. The solutions or suspensions are applied directlyto the nasal cavity by conventional means, for example, with a dropper,pipette or spray. The formulations may be provided in a single ormultidose form. In the latter case of a dropper or pipette, this may beachieved by the patient administering an appropriate, predeterminedvolume of the solution or suspension. In the case of a spray, this maybe achieved for example by means of a metering atomizing spray pump.

[0171] The compounds of the present invention may be formulated foraerosol administration, particularly to the respiratory tract andincluding intranasal administration. The compound will generally have asmall particle size for example of the order of five (5) microns orless. Such a particle size may be obtained by means known in the art,for example by micronization. The active ingredient is provided in apressurized pack with a suitable propellant such as a chlorofluorocarbon(CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

[0172] The compounds of the present invention can be formulated intransdermal or subcutaneous drug delivery devices. These deliverysystems are advantageous when sustained release of the compound isnecessary and when patient compliance with a treatment regimen iscrucial. Compounds in a transdermal delivery systems are frequentlyattached to a skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

[0173] The pharmaceutical preparations are preferably in unit dosageforms. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampoules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

[0174] Other suitable pharmaceutical carriers and their formulations aredescribed in Remington, (1995) The Science and Practice of Pharmacy(1995), edited by E. W. Martin, Mack Publishing Company, 19th edition,Easton, Pa. Representative pharmaceutical formulations containing acompound of the present invention are described in Examples 9-15.

EXAMPLES

[0175] The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Preparation 1 Preparation of a Compound of Formula 14-(5-oxo-[1,4]oxazepan-4-yl)-butyraldehyde

[0176] To a stirred suspension of sodium hydride (0.9 g, 37.5 mmole) indimethylformamide (50 mL) was added 1,4-oxazepan-2-one (30 mmole). Themixture was stirred at room temperature for 15 minutes, and then5-bromo-1-pentene (5.03 g, 33.7 mmole) was added slowly. The reactionmixture was stirred at room temperature for 30 minutes, and then at 80°C. for 16 hours. The solvent was removed under reduced pressure andwater was added to the residue. The mixture was extracted with diethylether, the organic phase was washed with water, dried (magnesiumsulfate) and concentrated to give 1-pent-4-enyl-oxazepan-2-one (5.5 g,)as an oil.

[0177] Osmium tetroxide (17 mg, 0.07 mmole) was added to1-pent-4-enyl-oxazepan-2-one (5.5 g, 28.3 mmole) in a mixture oftetrahydrofuran (100 mL) and water (50 mL) under ambient water bathcooling. The mixture was stirred for 5 minutes and solid sodiumperiodate (15.11 g, 70.65 mmole) was added in portions over 15 minutes.The reaction mixture was stirred for 3 hours and filtered. The filtratewas concentrated, saturated with solid sodium chloride, and extractedwith methylene chloride. The organic phase was dried (magnesium sulfate)and concentrated. Purification by silica gel chromatography, elutingwith chloroform, gave 4-(2-oxo-oxazepan-1-yl)-butyraldehyde (4.6 g).

[0178] Similarly, following the procedure described above in Preparation1, but optionally replacing 1,4-oxazepan-2-one with other appropriatecompounds of formula a and optionally replacing 5-bromo-1-pentene withother appropriate alkylating agents of the formula L(CH₂)_(n)CH═CH₂,wherein L is a leaving group such as halogen, and utilizingmodifications known to those skilled in the art, the additionalcompounds of formula 1 were prepared:

[0179] 5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butylester.

Preparation 2 Alternative Preparation of a Compound of Formula 15-Oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl Ester

[0180] To a suspension of 60% sodium hydride in mineral oil (0.2 g, 5mmole) in N,N-dimethylformamide (6 mL) was added5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.0 g, 4.67mmole). The reaction mixture was warmed at 50° C. for 5 minutes, andthen at room temperature for 15 minutes. To the resulting solution wasadded 4-bromobutyraldehyde dimethyl acetal (0.99 g, 5 mmole). After thereaction mixture was stirred at room temperature for 16 hours, thesolvent was removed, and the residue was partitioned between water andethyl acetate. The organic phase was washed with water, dried (magnesiumsulfate), and concentrated. The residue was dissolved in diethyl ether,and the suspension was filtered, and the filtrate was concentrated.Purification by silica gel chromatography, eluting with 2% methanol inchloroform, gave4-(4,4-dimethoxybutyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butylester (0.8 g,) as a heavy syrup. Nmr: (chloroform-¢) δ (ppm) 1.49, s,(9H); 2.64, m, 3H; 3.32, s (3H); 4.37, m, (1H).

[0181] A solution of4-(4,4-dimethoxybutyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butylester (3 g, 9.08 mmole) in glacial acetic acid containing 0.5 mL water(10 mL) was stirred at room temperature for 24 hours. The solution wasconcentrated at 35° C. under reduced pressure, and the residue waspartitioned between saturated aqueous sodium bicarbonate and diethylether. The organic phase was dried (magnesium sulfate), concentrated,and the residue recrystallized from diethyl ether/hexane to give5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester(0.85 g,), m.p. 86-87° C.

Preparation 3 Alternative Preparation of Compounds of Formula 1

[0182] To an ice-cooled solution of 1.93M phosgene in toluene (31 mL, 60mmole) was added dropwise a solution of 5-chloro-1-pentanol (4.9 g, 40mmole) and N,N-diethylaniline (5.97 g, 40 mmole) in toluene (40 mL). Thereaction mixture was stirred at ambient temperature for 4 hours. Themixture was filtered, and the filtrate was concentrated. The residue wastaken up in ethyl acetate, filtered, and the solution was added dropwiseto an ice-cooled solution of 4-aminobutyraldehyde diethylacetal (7.09 g,44 mmole) and triethylamine (4.45 g, 44 mmole) in ethyl acetate (60 mL).The reaction mixture was stirred at room temperature for 15 hours,filtered and concentrated. Purification by silica gel chromatography,eluting with 10% ethyl acetate in hexane, gave(4,4-diethoxybutyl)carbamic acid 5-chloro-pentyl ester (11.4 g,) as anoil.

[0183] To a solution of (4,4-diethoxybutyl)carbamic acid 5-chloro-pentylester (11.4 g, 44 mmole) dissolved in N,N-dimethylformamide (100 mL) wasadded de-oiled sodium hydride (1.01 g, 42.3 mmole). The reaction mixturewas stirred for 15 hours at room temperature, and then at 70° C. for 3hours. The mixture was diluted with water, saturated aqueous sodiumchloride was added, and extracted with diethyl ether. The organic phasewas washed with water, dried (magnesium sulfate), and concentrated.Purification by silica gel chromatography, gave3-(4,4-diethoxybutyl)-[1,3]oxazocan-2-one (2.03 g) as a viscous oil.

[0184] A mixture of 3-(4,4-diethoxybutyl)-[1,3]oxazocan-2-one (2 g, 7.3mmole) and 1.5 g Dowex 50W2-200 ion exchange resin in 3% aqueoustetrahydrofuran (30 mL) was heated under reflux for 24 hours. Themixture was filtered, and the filtrate was concentrated and dissolved indichloromethane. The solution was dried with magnesium sulfate andconcentrated to give 4-(2-oxo-[1,3]oxazocan-3-yl)-butyraldehyde (1.45 g)as a viscous oil which solidified.

3-(2-Oxo-tetrahydropyrimidin-1-yl)-propionaldehyde

[0185] To a stirred and ice-cooled solution of 3-aminopropionaldehydediethylacetal (5.88 g, 40 mmole) in diethyl ether (35 mL) was addeddropwise 3-chloropropyl isocyanate (4.78 g, 40 mmole). The reactionmixture was stirred at room temperature for 4 hours. The mixture wasconcentrated and dissolved in N,N-dimethylformamide (40 mL). To thissolution was added de-oiled sodium hydride (0.96 g, 40 mmole). Thereaction mixture was stirred at 70° C. for 18 hours, concentrated, takenup in diethyl ether (40 mL), and filtered. The filtrate was concentratedand purified by silica gel chromatography, eluting with hexane-ethylacetate-methanol (10:9.7:0.3), gave1-(3,3-diethoxypropyl)-tetrahydropyrimidin-2-one (9.05 g) as an oil.

[0186] A mixture of 1-(3,3-diethoxypropyl)-tetrahydropyrimidin-2-one (1g, 4.35 mmole), and 1.0 g Dowex 50W2-200 ion exchange resin in 3%aqueous tetrahydrofuran (30 mL) was heated under reflux for 24 hours.The mixture was filtered, the filtrate was concentrated and the residuedissolved in dichloromethane (30 mL), dried with magnesium sulfate, andconcentrated to give 3-(2-oxo-tetrahydropyrimidin-1-yl)-propionaldehyde(0.46 g).

Preparation 4 Preparation of a Compound of Formula 2 (R¹, R²═H,R³=propyl, p=2) Propyl-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine

[0187] To a solution of 3,4-dihydro-1-H-naphthalen-2-one (5 g, 34 mmol)in 1,2-dichloroethane (250 mL), propyl amine (2.8 mL, 34 mmol) wasadded, followed by addition of sodium triacetoxyborohydride (22 g, 102mmol). The reaction was stirred at ambient temperature under nitrogenfor 24 hours, at which time it was concentrated in vacuo. The remainingsolid was partitioned between 1M sodium hydroxide and ethyl acetate. Theethyl acetate was washed with brine, dried over magnesium sulfate, andfiltered. The filtrate was acidified with 1M HCl in ether and 6.3 g ofpropyl-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine was collected as apale pink precipitate.

Example 1 Preparation of a Compound of Formula IB as Described in SchemeB3-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one(19)

[0188]

[0189] To a solution of 7-Methoxy-3,4-dihydro-1-H-naphthalen-2-one (5.0g, 28.4 mmol) and propylamine (2.8 mL, 34 mmol, 1.2 eq) in1,2-dichloroethane (150 mL) under inert atmosphere was added sodiumtriacetoxyborohydride (15 g, 71 mmol, 2.5eq) in a single portion. Thereaction was allowed to stir at room temperature for 20 h thenconcentrated in-vacuo. The residue was partitioned between 10% aq. KOH(150 mL) and ethyl acetate (75 mL). The organic layer was washed withbrine, dried and concentrated. The resulting material was dissolved indiethyl ether (100 mL) and treated with 1M HCl in ether (28.4 ML). Thesolid was collected and dried under vacuum to afford 6.23 g of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl-propyl-amine ashydrochloride salt.

[0190] To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine(ca.13 mg 50 mmole), was added 440 μL solution of4-(2-oxo-[1,3]oxazinan-3-yl)-butyraldehyde (0.125 M in 1,2dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 Mslurry of sodium triacetoxyborohydride in 1,2 dichloroethane. Thereaction was shaken at room temperature for 48 h. After quenching with 2mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL waterand ethyl acetate to workup flasks. The organic phase was washed, driedand concentrated. Purification by chromatography yielded3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one19, MS: 375 ([M+H]⁺).

[0191] Similarly, following the procedure described above in Example 1,but optionally replacing 4-(2-oxo-[1,3]oxazinan-3-yl)-butyraldehyde withother appropriate compounds of formula 1 b and optionally replacing7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinX is O, were prepared as trifluoroacetic acid salts:

[0192]3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one20, MS: 389 ([M+H]⁺);

[0193]3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one28, MS: 419 ([M+H]⁺);

[0194]3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one29, MS: 405 ([M+H]⁺);3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazocan-2-one31, MS: 403 ([M+H]⁺);

[0195]3-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one57, MS: 381 ([M+H]⁺);

[0196]3-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one58, MS: 395 ([M+H]⁺);

[0197]3-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazocan-2-one60, MS: 409 ([M+H]⁺);

[0198]3-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one69, MS: 404 ([M+H]⁺);

[0199]3-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one70, MS: 390 ([M+H]⁺);

[0200]3-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one118, MS: 389 ([M+H]⁺);

[0201]3-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one145, MS: 403 ([M+H]⁺);

[0202]3-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one147, MS: 389 ([M+H]⁺);

[0203]3-{4-[(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one161, MS: 425 ([M+H]⁺);

[0204]3-{4-[(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one162, MS: 439 ([M+H]⁺); or

[0205]3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one174, MS: 419 ([M+H]⁺).

Example 2

[0206] Preparation of a Compound of Formula IC as Described in Scheme C

1-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one(3)

[0207]

[0208] To a solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-aminehydrochloride prepared as described in Example 1 (500 mg, 2 mmol, 1eq)and triethylamine (0.3 mL, 2.2 mmol, 1.1 eq.) in 1,2-dichlororethane (20mL) under inert atmosphere was added the3-oxo-4-(4-oxo-butyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester(550 mg, 2 mmol, 1 eq.) in a single portion followed by the sodiumtriacetoxyborohydride (650 mg, 3 mmol, 1.5 eq.). The reaction wasstirred at room temperature for 20 hr, concentrated in-vacuo and thenpartitioned between 10% KOH (40 mL) and ethyl acetate (75 mL), theorganic layer was washed with brine, dried (MgSO₄) and concentrated.Purification by chromatography provided 858 mg of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester.

[0209] To a solution of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester (858 mg, 1.64 mmol) in methylene chloride (25 mL)was added trifluoroacetic acid (5 mL) in a single portion, and thereaction was stirred at room temperature for 30 min. The mixture wasconcentrated to dryness in-vacuo, dissolved in water and treated with15% aq. KOH The solution was extracted with ethyl acetate, washed withbrine, dried (MgSO₄) and concentrated to dryness. The free base (682 mg,1.7 mmol) was taken up in diethyl ether (30 mL) and treated with 1MHCl/ether (3.4 mL). The solid was collected and dried under vacuum toafford the product 3 as a dihydrochloride (767 mg, 98% yield), MS 374([M+H]⁺).

[0210] Similarly, following the procedures described above in Example 2,but optionally replacing3-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl esterwith other appropriate compounds of formula 1d and optionally replacing(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinY is NH were prepared:

[0211]1-{4-[(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one1, MS: 388 ([M+H]⁺);

[0212]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one12, MS: 374 ([M+H]⁺);

[0213]1-{4-[ethyl-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-butyl}-[1,4]diazepan-2-one15, MS: 374 ([M+H]⁺);

[0214]1-{3-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-propyl}-[1,4]diazepan-2-one23, MS: 374 ([M+H]⁺);

[0215]1-{4-[(7-methanesulfonyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one25, MS: 418 ([M+H]⁺);

[0216]1-{4-[(7-isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one36, MS: 402 ([M+H]⁺);

[0217]1-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one54, MS: 480 ([M+H]⁺);

[0218]1-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one63, MS: 394 ([M+H]⁺);

[0219]1-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one72, MS: 403 ([M+H]⁺);

[0220]1-{3-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-propyl}-[1,4]diazepan-2-one74, MS: 389 ([M+H]⁺);

[0221]1-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one89, MS: 374 ([M+H]⁺);

[0222]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one91, MS: 374 ([M+H]⁺);

[0223]1-{4-[(R)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one92, MS: 388 ([M+H]⁺);

[0224]1-{4-[(S)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one93, MS: 388 ([M+H]⁺);

[0225]1-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one111, MS: 388 ([M+H]⁺);

[0226]1-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one112, MS: 402 ([M+H]⁺);

[0227]1-{4-[(6-isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one114, MS: 402 ([M+H]⁺);

[0228]1-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one148, MS: 388 ([M+H]⁺);

[0229]1-{5-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-piperazin-2-one154, MS: 418([M+H]⁺);

[0230]1-{5-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-2-one155, MS: 432([M+H]⁺);

[0231]1-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one156, MS: 418([M+H]⁺);

[0232]1-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one166, MS: 404([M+H]⁺);

[0233]1-{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one171, MS: 436([M+H]⁺); or

[0234]1-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one173, MS: 418([M+H]⁺).

Example 3 Alternative Preparation of a Compound of Formula IC asDescribed in Scheme C4-(2-Dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one(64)

[0235]

[0236] To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-aminehydrochloride (150 mg, 0.3 mmol) and triethylamine (0.2 mL, 1.3 mmol) inmethylene chloride (10 mL) under inert atmosphere was added2-chloroethane sulfonyl chloride (0.03 mL, 0.3 mmol). The reactionmixture was allowed to stir at room temperature for 1 hour, and wasquenched with 2% sodium carbonate. The organic layer was dried (MgSO₄),filtered and concentrated in-vacuo to afford4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-sulfonylchloride as a yellow oil.

[0237] To4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-sulfonylchloride (0.3 mmol) and triethylamine (0.1 mL, 0.6 mmol,) in methylenechloride (15 mL) under inert atmosphere was added dimethyl amine 2 M inTHF (0.17 mL, 0.34 mmol). The reaction was allowed to stir at roomtemperature for 20 h, then concentrated in-vacuo. The remaining oil waspurified over silica gel to afford a clear oil which was taken up indiethyl ether (10 mL) and treated with 1M HCl in ether. The solid wascollected and dried under vacuum to afford4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-oneas a dihydrochloride (83 mg) 64, MS: 523([M+H]⁺).

[0238] Similarly, following the procedures described above in Example 3,but optionally replacing1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-onewith other free amine compounds of Formula IC, and optionally replacing2-chloroethane sulfonyl chloride with other appropriate acylating,alkylating, or sulfonylating agents, and utilizing modifications knownto those skilled in the art, the additional compounds of Formula Iwherein Y is NR⁴ were prepared:

[0239]4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one2, MS: 523([M+H]⁺);

[0240]4-(4-fluoro-benzoyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one121, MS: 496([M+H]⁺);

[0241]4-(2,2-dimethyl-propionyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one122, MS: 458([M+H]⁺);

[0242]4-isobutyryl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one123, MS: 444([M+H]⁺);

[0243]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-(thiophene-2-carbonyl)-piperazin-2-one124, MS: 484([M+H]⁺);

[0244]4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid diethylamide 125, MS: 473([M+H]⁺);

[0245]4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid dimethylamide 126, MS: 445([M+H]⁺);

[0246]4-acetyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one127, MS: 416([M+H]⁺);

[0247]4-(3,5-dimethyl-isoxazole-4-carbonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one128, MS: 497([M+H]⁺);

[0248]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-(thiophene-2-sulfonyl)-piperazin-2-one129, MS: 520([M+H]⁺);

[0249]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-trifluoromethanesulfonyl-piperazin-2-one130, MS: 506([M+H]⁺);

[0250]4-benzenesulfonyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one131, MS: 514([M+H]⁺);

[0251]4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-sulfonicacid dimethylamide 132, MS: 481 ([M+H]⁺);

[0252]4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid phenylamide 133, MS: 493([M+H]⁺);

[0253]4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid ter-butylamide 134, MS: 473([M+H]⁺);

[0254]4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-piperazine-1-carboxylicacid methylamide 135, MS: 431 ([M+H]⁺);

[0255]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-thiophen-2-ylmethyl-piperazin-2-one136, MS: 470([M+H]⁺);

[0256]4-ethyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one137, MS: 470([M+H]⁺);

[0257]4-(1-methanesulfonyl-piperidin-4-ylmethyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one138, MS: 549([M+H]⁺); or

[0258]4-methanesulfonyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one139, MS: 452([M+H]⁺).

Example 4 Alternative Preparation of a Compound of Formula IC asDescribed in Scheme C4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one(17)

[0259]

[0260] To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine(ca. 13 mg 50 μmole) as described in Example 1, was added 440 μLsolution of 4-(2-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.125 M in 1,2dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 Mslurry of sodium triacetoxyborohydride in 1,2 dichloroethane. Thereaction was shaken at room temperature for 48 h. After quenching with 2mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL waterand ethyl acetate to workup flasks. The organic phase was washed, driedand concentrated. Purification by chromatography yielded4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one17, MS: 389([M+H]⁺);

[0261] Similarly, following the procedure described above in Example 4,but optionally replacing 4-(2-oxo-[1,4]oxazepan-4-yl)-butyraldehyde withother appropriate compounds of formula 1c and optionally replacing(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinY is O:

[0262]4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one27, MS: 419([M+H]⁺);

[0263]4-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one55, MS: 395([M+H]⁺);

[0264]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-4-(morpholine-4-carbonyl)-piperazin-2-one120, MS: 487([M+H]⁺); or

[0265]4-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-3-one144, MS: 403([M+H]⁺).

Example 5 Preparation of a Compound of Formula ID as Described in SchemeD4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one(5)

[0266]

[0267] To a solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine prepared asdescribed in Example 1 (800 mg, 3.3 mmol, 1 eq) in 1,2-dichlororethane(40 mL) under inert atmosphere was added5-oxo-4-(4-oxo-butyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester(1.0 g, 3.6 mmol, 1.1 eq.) in a single portion followed by the sodiumtriacetoxyborohydride (1.7 g, 8.25 mmol, 2.5 eq.). The reaction wasstirred at room temperature for 20 hr, concentrated in-vacuo and thenpartitioned between 10% KOH (50 mL) and ethyl acetate (100 mL). Theorganic layer was washed with brine, dried (MgSO₄) and concentrated.Purification by silica gel chromatography gave 1.1 g of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-5-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester.

[0268] To4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-5-oxo-[1,4]diazepane-1-carboxylicacid tert-butyl ester (800 mg, 1.64 mmol) in methylene chloride (15 mL)was added trifluoroacetic acid (5 mL) in a single portion and thereaction was stirred at room temperature for 30 min. The mixture wasconcentrated to dryness in-vacuo, dissolved in water (40 mL) and treatedwith 15% aq. KOH (20 mL). The solution was extracted with ethyl acetate,washed with brine, dried (MgSO₄) and concentrated in-vacuo. The freebase (636 mg, 1.64 mmol) was taken up in diethyl ether (30 mL) andtreated with 1M HCl in ether (3.3 mL). The solid was collected and driedunder vacuum to afford 732 mg of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one5 as a dihydrochloride salt. MS: 374([M+H]⁺).

[0269] Similarly, following the procedures described above in Example 5,but optionally replacing5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl esterwith other appropriate compounds of formula 1f and optionally replacing(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinZ is NH were prepared:

[0270]4-{4-[(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one4, MS: 388([M+H]⁺);

[0271]N-(2-{ethyl-[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-amino}-indan-5-yl)-4-methanesulfonyl-benzamide7, MS: 388([M+H]⁺);

[0272]4-(4-{propyl-[6-(thiazole-2-sulfonyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-butyl)-[1,4]diazepan-5-one8, MS: 505([M+H]⁺);

[0273]4-{4-[ethyl-(5-methoxy-indan-2-yl)-amino]-butyl}-[1,4]diazepan-5-one 9,MS: 360([M+H]⁺);

[0274]4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one10, MS: 418([M+H]⁺);

[0275] 4-[4-(ethyl-indan-2-yl-amino)-butyl]-[1,4]diazepan-5-one 11; MS:330([M+H]⁺).

[0276]1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-piperazin-2-one13, MS: 374([M+H]⁺);

[0277]4-{4-[ethyl-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-butyl}-[1,4]diazepan-5-one16, MS: 374([M+H]⁺);

[0278]4-{4-[(7-isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one22, MS: 416([M+H]⁺);

[0279] methanesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 38, MS: 452([M+H]⁺);

[0280] ethanesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 39, MS: 466([M+H]⁺);

[0281] propane-1-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 40, MS: 480([M+H]⁺);

[0282] propane-2-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 41, MS: 480([M+H]⁺);

[0283] trifluoro-methanesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 42, MS: 506([M+H]⁺);

[0284] benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 43, MS: 514([M+H]⁺);

[0285] thiophene-2-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 44, MS: 520([M+H]⁺);

[0286] phenyl-methanesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 45, MS: 528([M+H]⁺);

[0287] 3,5-dimethyl-isoxazole-4-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 46, MS: 533([M+H]⁺);

[0288] 4-methoxy-benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 47, MS: 544([M+H]⁺);

[0289] 4-chloro-benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 48, MS: 548([M+H]⁺);

[0290] 4-chloro-benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 49 MS: 548([M+H]⁺);

[0291] 3-chloro-benzenesulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 50, MS: 548([M+H]⁺);

[0292] dimethyl-sulfamic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 51, MS: 481 ([M+H]⁺);

[0293] pyrrolidine-1-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 52, MS: 507([M+H]⁺);

[0294]4-{4-[(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one61, MS: 494([M+H]⁺);

[0295]4-{4-[(7-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one65, MS: 374([M+H]⁺);

[0296] 1-Methyl-1H-imidazole-4-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 66, MS: 518([M+H]⁺);

[0297]4-{4-[(7-Phenoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one67, MS: 450([M+H]⁺);

[0298] trifluoro-acetic acid;4-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one71, MS: 403([M+H]⁺);

[0299]4-{5-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one73, MS: 417([M+H]⁺);

[0300]4-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one75, MS: 402([M+H]⁺);

[0301]N-(7-{[4-(7-Oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-propionamide76, MS: 429([M+H]⁺);

[0302] cyclopropanecarboxylic acid(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide77, MS: 441 ([M+H]⁺);

[0303]N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-isobutyramide78 MS: 443([M+H]⁺);

[0304]2,2-dimethyl-N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-propionamide79, MS: 457([M+H]⁺);

[0305]3,3-dimethyl-N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-butyramide80, MS: 457([M+H]⁺);

[0306] pyrrolidine-1-sulfonic acid(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide81, MS: 506 ([M+H]⁺);

[0307]4-(4-{[7-(2,2-dimethyl-propylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-amino}-butyl)-[1,4]diazepan-5-one82, MS: 443 ([M+H]⁺);

[0308]4-{4-[(7-cyclohexylamino-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one83, MS: 455 ([M+H]⁺);

[0309]1-isopropyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-urea84, MS: 458 ([M+H]⁺);

[0310]1-ter-butyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-urea85, MS: 472 ([M+H]⁺);

[0311]1-benzoyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-urea86, MS: 520 ([M+H]⁺);

[0312]4-{4-[(S)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one87, MS: 388 ([M+H]⁺);

[0313]4-{5-[(R)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one88, MS: 402 ([M+H]⁺);

[0314]4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one90, MS: 388 ([M+H]⁺);

[0315] ethanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 94, MS: 466 ([M+H]⁺);

[0316] propane-2-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 95, MS: 466 ([M+H]⁺);

[0317] benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 96, MS: 514 ([M+H]⁺);

[0318] phenyl-methanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 97, MS: 528 ([M+H]⁺);

[0319] 4-methoxy-benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 98, MS: 544 ([M+H]⁺);

[0320] 2-chloro-benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 99, MS: 548 ([M+H]⁺);

[0321] pyrrolidine-1-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 100, MS: 507 ([M+H]⁺);

[0322] methanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 101, MS: 452 ([M+H]⁺);

[0323] propane-1-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 102, MS: 480 ([M+H]⁺);

[0324] trifluoro-methanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 103, MS: 506 ([M+H]⁺);

[0325] 1-methyl-1H-imidazole-4-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 104, MS: 518 ([M+H]⁺);

[0326] thiophene-2-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yleste105, MS: 520 ([M+H]⁺);

[0327] 3,5-dimethyl-isoxazole-4-sulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 106, MS: 533 ([M+H]⁺);

[0328] 4-chloro-benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 107, MS: 548 ([M+H]⁺);

[0329] 3-chloro-benzenesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 108, MS: 548 ([M+H]⁺);

[0330] dimethyl-sulfamic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 109, MS: 548 ([M+H]⁺);

[0331]4-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino)-butyl}-[1,4]diazepan-5-one110, MS: 402 ([M+H]⁺);

[0332]4-{4-[(6-isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-(1,4]diazepan-5-one113, MS: 416 ([M+H]⁺); trifluoro-methanesulfonic acid6-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 140, MS: 508 ([M+H]⁺);

[0333]4-{4-[(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one141, MS: 436 ([M+H]⁺);

[0334]4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one142, MS: 402 ([M+H]⁺);

[0335]4-{4-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one150, MS: 402 ([M+H]⁺);

[0336]4-{5-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one152, MS: 416 ([M+H]⁺);

[0337]4-{3-[(6-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-propyl}-[1,4]diazepan-5-one153, MS: 388 ([M+H]⁺);

[0338]4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one157, MS: 436 ([M+H]⁺);

[0339] dimethyl-carbamic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 167, MS: 445 ([M+H]⁺);

[0340] morpholine-4-carboxylic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 168, MS: 487 ([M+H]⁺);

[0341] isopropyl-carbamic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 169, MS: 459 ([M+H]⁺);

[0342] propyl-carbamic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 170, MS: 459 ([M+H]⁺); or

[0343]4-{5-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one172, MS: 432 ([M+H]⁺).

Example 6 Alternative Preparation of a Compound of Formula ID asDescribed in Scheme D1-(2-Dimethylamino-ethanesulfonyl)-4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one(24)

[0344]

[0345] To a solution of4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-onedihydrochloride (732 mg, 1.6 mmol), prepared as in Example 1, andtriethylamine (0.78 mL, 5.6 mmol) in methylene chloride (20 mL) underinert atmosphere was added 2-chloroethane sulfonyl chloride (0.17 mL,1.6 mmol). The reaction mixture was allowed to stir at room temperaturefor 4 hours, and was quenched with 2% sodium carbonate. The organiclayer was dried (MgSO₄), filtered and concentrated in vacuo to affordthe chloroethylsulfonamide as a yellow oil.

[0346] To the chloroethylsulfonamide (1.6 mmol) and triethylamine (0.5mL, 3.6 mmol, 2.25 eq.) in methylene chloride (30 mL) under inertatmosphere was added dimethylamine hydrochloride (148 mg, 1.8 mmol). Thereaction was allowed to stir at room temperature for 20 hours, thenconcentrated in vacuo. The remaining oil was chromatographed over silicagel to afford the free base as a clear oil. The free base (215 mg, 0.41mmol) was taken up in diethyl ether and treated with 1M HCl in ether(0.82 mL). The solid was collected and dried under vacuum to afford4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one24 as a dihydrochloride (238 mg). (M+H)⁺=523

[0347] Similarly, following the procedures described above in Example 6,but optionally replacing4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-onedihydrochloride with other free amine compounds of Formula ID, andoptionally replacing chloroethylsulfonamide with other appropriateacylating, alkylating, or sulfonylating agents, and utilizingmodifications known to those skilled in the art, the additionalcompounds of Formula I wherein Z is NR⁴ were prepared:

[0348]1-(2-dimethylamino-ethanesulfonylmethyl)-4-{4-[(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one6, MS: 523 ([M+H]⁺).

Example 7 Alternative Preparation of a Compound of Formula ID asDescribed in Scheme D4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one(18)

[0349]

[0350] To (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine(ca.13 mg 50 μmole) prepared as described in Example 1, was added 440 μLsolution of 4-(6-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.125 M in 1,2dichloroethane), 30 μL diisopropylethylamine (DIEA) and 300 μL of 0.25 Mslurry of sodium triacetoxyborohydride in 1,2 dichloroethane. Thereaction was shaken at room temperature for 48 h. After quenching with 2mL 2% NaOH, the reaction mixture was transferred along with 0.5 mL waterand ethyl acetate to workup flasks. The organic phase was washed, driedand concentrated. Purification by chromatography yielded3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazinan-2-one18, MS: 375 ([M+H]⁺).

[0351] Similarly, following the procedure described above in Example 7,but optionally replacing 4-(6-oxo-[1,4]oxazepan-4-yl)-butyraldehyde withother appropriate compounds of formula 1 e and optionally replacing(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine with otherappropriate compounds of formula 2, and utilizing modifications known tothose skilled in the art, the additional compounds of Formula I whereinZ is 0 were prepared:

[0352]4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one26, MS: 419([M+H]⁺);⁴-{4-[(7-Isopropoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one34, MS: 417 ([M+H]⁺);

[0353]4-{4-[(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one56, MS: 395 ([M+H]⁺);

[0354]4-{4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one68, MS: 404 ([M+H]⁺);

[0355]4-{4-[(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one116, MS: 403 ([M+H]⁺);

[0356]4-{4-[(6-Ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one143, MS: 403 ([M+H]⁺); or4-{4-[(6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]oxazepan-5-one160, MS: 439 ([M+H]⁺).

Example 8

[0357] Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate  0.5%

[0358] The ingredients are mixed and dispensed into capsules containingabout 100 mg each; one capsule would approximate a total daily dosage.

Example 9

[0359] Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0%  Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5%  PVP (polyvinylpyrrolidine) 1.0%

[0360] The ingredients are combined and granulated using a solvent suchas methanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Example 10

[0361] Composition for Oral Administration Ingredient Amount Activecompound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben0.15 g Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70%solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 mLColorings 0.5 mg Distilled water q.s. to 100 mL

[0362] The ingredients are mixed to form a suspension for oraladministration.

Example 11

[0363] Parenteral Formulation (IV) Ingredient % wt./wt. Activeingredient 0.25 g Sodium Chloride qs to make isotonic Water forinjection to 100 mL

[0364] The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Example 12

[0365] Suppository Formulation Ingredient % wt./wt. Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

[0366] The ingredients are melted together and mixed on a steam bath,and poured into molds containing 2.5 g total weight.

Example 13

[0367] Topical Formulation Ingredients grams Active compound 0.2-2 Span60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

[0368] All of the ingredients, except water, are combined and heated toabout 60° C. with stirring. A sufficient quantity of water at about 60°C. is then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. about 100 g.

Example 14 Nasal Spray Formulations

[0369] Several aqueous suspensions containing from about 0.025-0.5percent active compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

EXAMPLE 15 Radioligand Binding Studies

[0370] The inhibitory activity of compounds of this invention in vitrowas determined using a modification of the method described in Hegde, S.S. et al. (1997) Br. J. Pharmacol., 120, 1409-1418.

[0371] Cell membranes from Chinese hamster ovary cells expressing therecombinant human muscarinic receptors (m₁-m₅) were employed. The assayswere conducted with the radioligand [³H]N-methyl scopolamine(0.4 nM,specific activity 84 Ci-mmol-1) in a final volume of 0.25 mL Tris-Krebsbuffer. Non-specific binding was defined with 1 μM atropine. Assays wereperformed using scintillation proximity assay technology.Competition-displacement curves were generated using 10 concentrationsof test compounds and were analyzed by iterative curve fitting to a fourparameter logistic equation. pIC₅₀ values (-log of the IC₅₋₀) wereconverted to pKi values using the Cheng-Prusoff equation.

[0372] Compounds of this invention were active in this assay.

Example 16 Oxotremorine/Pilocarpine-Induced Salivation (OIS/PIS) Modelin Anesthetized Rats.

[0373] Female Sprague-Dawley rats (Charles-River, 200-300 g) rats wereanesthetized with urethane (1.5 g/kg, sc) and were tracheotomized. Onefemoral vein was cannulated for drug administration. After a one hourstabilization period, rats were pre-treated with methoctramine (only forOIS) to antagonize M₂ receptor mediated bradycardia. Each animal wasdosed, intravenously, with a single dose of the vehicle or the referencecompound. Ten minutes later, pre-weighed cotton pads were placed in theanimals mouth following which they were dosed with vehicle oroxotremorine (0.1 mg/kg, iv)/pilocarpine (1 mg/kg, iv). Fresh cottonpads were placed at 5 minutes post-oxotremorine/pilocarpine and salivacollected for an additional 5 minutes. The cotton pads (5 and 10-minuteperiod) were then re-weighed to determine the amount of saliva secretedduring the 10-minute period.

[0374] All oxotremorine/pilocarpine treated groups were compared usingone-way analysis of variance. Pair-wise comparisons were made usingDunnett's test. The ranked data (non-parametric technique) or actuallevels of the data (parametric technique) are applied in the analysisdepending upon the results of the Bartlett's test, which testshomogeneity of variances. The vehicle/oxotremorine group andvehicle/pilocarpine was compared to the vehicle/vehicle group usingWilcox on rank-sum test. An estimate of the ID₅₀ for each compound withrespect to the 10 minute overall secretion weight for each animal wasobtained. The sigmoidal model is in the form of

Resp=min+(max−min)/(1+(dose/ID ₅₀)**N)

[0375] where ID₅₀ is the dose to achieve half the maximal response, N isthe curvature parameter and max is the max response for the doseresponse curve. The minimum response was fixed at 0 in the model.

[0376] Compounds of this invention were active in this assay.

EXAMPLE 17 Inhibition of Volume-Induced Contractions in Rats

[0377] The muscarinic receptor inhibitory activity of compounds of thisinvention in vivo was determined in rats using a modification of themethod described in Hegde, S. S. et al.(1996) Proceedings of the 26thAnnual Meeting of the International Continence Society (August27th-30th), Abstract 126.

[0378] Female Sprague-Dawley rats were anesthetized with urethane andinstrumented for intravenous administration of drugs and, in some cases,measurement of arterial pressure, heart rate and intra-bladder pressure.The effect of test compounds on volume-induced bladder contractions wasdetermined in separate groups of animals. Volume-induced reflex bladdercontractions were induced by filling the bladder with saline. The testcompounds were administered intravenously in a cumulative manner at10-minute intervals. Atropine (0.3 mg/kg, iv) was administered at theend of the study as a positive control.

[0379] Compounds of this invention were active in this assay.

EXAMPLE 18 Anti-Muscarinic Activity in Anesthetized Dogs

[0380] The muscarinic receptor inhibitory activity of compounds of thisinvention in vivo was determined in dogs using a modification of themethod described in Newgreen, D. T. et al.,(1996) J. Urol., 155 (Suppl.5), 1156.

[0381] Female beagles (Marshall Farms, North Rose, N.Y.) were fasted for18 hours prior to the experiment; water was allowed ad libitum. On theday of the experiment, dogs were anesthetized and maintained onpentobarbital (36 mg/kg, iv initially, then 5-10 mg/kg, iv formaintenance). Intravenous fluids were also administered to the dog forthe remainder of the experiment. The dogs were artificially ventilated,via an endotracheal tube, with an Harvard respirator (Model 613). Bothfemoral veins and one femoral artery was cannulated for drugadministration and blood pressure measurement, respectively. Bloodpressure was measured with a Gould transducer (Model P23XL) and recordedon a Gould recorder (Model 3400). A sublingual incision was made toexpose the left mandibular duct, which was then cannulated for thecollection of saliva into pre-weighed vials. The left salivary gland wasexposed via a submandibular incision. The chorda-lingual nerve wasisolated and had a bipolar electrode placed on it for stimulation. Testresponses to chorda-lingual nerve stimulation were obtained to confirmproper electrode placement.

[0382] After completion of surgery, physostigmine (180 μg/kg/hr, iv) (acholinesterase inhibitor) was infused for the remainder of theexperiment. Following a one hour stabilization period, two controlchorda-lingual nerve stimulations were performed at 12 Hz, 10 V, 0.5 msduration (Grass S48). The chorda-lingual nerve was stimulated for 20seconds and 2 minutes, respectively, with a minimum of 10 minuteinterval between each set of stimulations. After two consistent controlresponses were obtained, the vehicle or the reference compound was dosedin a cumulative fashion, 3 minutes prior to each stimulation of thechorda-lingual nerve. Experiments in which consistent salivationresponses could not be obtained were not included in the analysis.Atropine (1.0 mg/kg, iv) was given as a positive control at the end ofthe study.

[0383] Mean arterial blood pressure was calculated as Diastolic arterialpressure+(Systolic arterial pressure−Diastolic arterial pressure)/3.Heart rate was derived from the pressure pulse. Saliva was collected inpre-weighed vials and weighed after each collection to determine thevolume of saliva secreted. Inhibition of salivary gland responses wereexpressed as a percent of the effect of atropine (1 mg/kg, iv).

[0384] ED50 Estimation

[0385] For % max inhibition salivation, parameter estimation wasperformed using a nonlinear mixed model. The method was implementedusing PROC NLIN initially and PROC MIXED iteratively. This procedureassumed the following sigmoidal dose-response model:${Response} = {{Min} + \frac{{Max} - {Min}}{1 + 10^{- \frac{({x - \mu})}{\sigma}}}}$

[0386] where response=% max inhibition bladder contraction at peak,x=log₁₀ dose of treatment and the 4 parameters were: log₁₀ ED50 (μ),maximum and minimum response (Max and Min), and curvature (σ). Theminimum was assumed 0%. This method assumed compound symmetry for thecovariance structure. It was an iterative curve-fitting procedure thataccounted for the dependence between multiple measurements from the sameanimal, and estimated the desired parameters and their confidence limitsby adjusting its error calculations to account for within subjectcorrelation.

[0387] Baseline Comparisons

[0388] To compare each dose to baseline control for every variable, atwo-way ANOVA with main effects of subject and treatment was performed,followed by a pair t-test at each dose level. If the overall treatmenteffect was not significant (p-value>0.05) in ANOVA, a Bonferroniadjustment for p-values was used for the p-value of pair t-test at eachdose.

[0389] Compounds of this invention were active in this assay.

[0390] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound comprising Formula I

wherein: R¹, and R² are independently in each occurrence hydrogen,halogen, (C₁₋₆)-alkyl, —OR′, —SR′, —NR′R″, —SOR′, —SO₂R′, —COOR′,—OCOR′, —OCONR′R″, —OSO₂R′, —OSO₂NR′R″; —NR′SO₂R″, —NR′COR″, —SO₂ NR′R″, —SO₂(CH₂)₁₋₃CON R′R″, —CON R′R″, cyano, haloalkyl, or nitro; or R′and R″ are independently in each occurrence hydrogen, (C₁₋₆)-alkyl,substituted lower alkyl, aryl, heterocyclyl, heteroaryl,aryl-(C₁₋₃)-alkyl, heteroaryl-(C₁₋₃)-alkyl, heterocyclyl-(C₁₋₃)-alkyl,cycloalkylalkyl, cycloalkyl, or R′ and R″ together with the nitrogenthey are attached may also form a 5- to 7-membered ring, optionallyincorporating one additional ring heteroatom chosen from N, O orS(O)₀₋₂; R³ is independently in each occurrence (C₁₋₆) alkyl, (C₁₋₆)alkenyl, (C₁₋₆) alkynyl, or cycloalkyl; or one of X, Y or Z isindependently S, O, or N—R⁴, the others are CH₂; R⁴ is hydrogen,(C₁₋₆)-alkyl, haloalkyl, aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl,—(C₁₋₆)—CR′R′R′, —COOR′, —SO₂R′, —C(O)R′, —SO₂(CH₂)₀₋₃NR′R″, —CONR′R″,or —PO(OR′)₂, wherein R′ and R″ are as defined above; p is an integerfrom 1 to 3 inclusive; m is an integer from 0 to 3 inclusive; n is aninteger from 1 to 6 inclusive; or prodrugs, individual isomers, racemicor non-racemic mixtures of isomers, or pharmaceutically acceptable saltsor solvates thereof.
 2. The compound of claim 1, wherein p is
 2. 3. Thecompound of claim 1, wherein n is
 3. 4. The compound of claim 2, whereinn is
 3. 5. The compound of claim 2, wherein one of X, Y or Z is NR⁴, andthe others are CH₂.
 6. The compound of claim 5, wherein R⁴ is hydrogen.7. The compound of claim 2, wherein m is
 1. 8. The compound of claim 2,wherein m is
 2. 9. The compound of claim 7, wherein Y is NR⁴, and X andZ are CH₂.
 10. The compound of claim 9, wherein Y is NH, and X and Z areCH₂.
 11. The compound of claim 8, wherein one of X, Y or Z is NR⁴ andthe others are CH₂.
 12. The compound of claim 11, wherein R⁴ is H. 13.The compound of claim 3, wherein one of X, Y or Z is NR⁴ and the othersare CH₂.
 14. The compound of claim 13, wherein p is
 2. 15. The compoundof claim 14, wherein one of X, Y or Z is NH and the others are CH₂. 16.The compound of claim 14, wherein m is
 2. 17. The compound of claim 16,wherein X is NH, and Y and Z are CH₂.
 18. The compound of claim 16,wherein Y is NH, and X and Z are CH₂.
 19. The compound of claim 16,wherein Z is NH, and X and Y are CH₂.
 20. The compound of claim 2,wherein m is 2, n is 3, and one of X, Y or Z is O and the others areCH₂.
 21. The compound of claim 1 comprising3,5-dimethyl-isoxazole-4-sulfonic acid7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester;4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one;4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one;1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;1-{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;or3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one,or a prodrug, an individual isomer, a racemic or non-racemic mixture ofisomers, or pharmaceutically acceptable salt or solvate thereof.
 22. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 in admixture with a pharmaceutically acceptablecarrier.
 23. The pharmaceutical composition of claim 22, wherein thecompound is suitable for administration to a subject having a diseasestate which is alleviated by treatment with a M2/M3 muscarinic receptorantagonist.
 24. A method of treatment comprising administering to asubject in need of such treatment, a therapeutically effective amount ofat least one compound of claim
 1. 25. A method of treatment comprisingadministering to a subject in need of such treatment, a therapeuticallyeffective amount of the composition of claim
 20. 26. The method oftreatment of claim 24, wherein the disease state is alleviated with aM2/M3 muscarinic antagonist.
 27. The method of treatment of claim 26,wherein the disease state is associated with smooth muscle disorderscomprising diseases of the genitourinary or gastrointestinal tract, orof respiratory states.
 28. The method of treatment of claim 27, whereinthe disease state is associated with the genitourinary tract.
 29. Themethod of treatment of claim 28, wherein the disease state comprisesoveractive bladder, detrusor hyperactivity, urgency, frequency, reducedbladder capacity, incontinence episodes, changes in bladder capacity,micturition threshold, unstable bladder contractions, sphinctericspasticity, outlet obstruction, outlet insuffciency, pelvichypersensitivity, idiopathic conditions or detrusor instability.
 30. Themethod of treatment of claim 27, wherein the disease state comprisesrespiratory states from allergies or asthma.
 31. The method of treatmentof claim 27, wherein the disease state comprises gastrointestinal tractdisorders.
 32. A process for preparing a compound as claimed in claim 1which process comprises reacting a compound having a general formula

with a compound of general formula

to provide a compound of Formula I

wherein R¹, R², R^(3,) p, m, n, X, Y, and Z are as defined in claim 1.